Cardiometabolic syndrome (CMS) is known as the collective impact of type 2 diabetes (T2D), hypertension (HTN), and obesity, and is one of the biggest health challenges facing the world today. DNA methylation, the addition of a methyl group to cytosine or adenine nucleotides, varies with aging and with environmental exposures, and is a critical epigenetic mediator of gene expression. CMS has a variety of local and systemic manifestations, all of which are likely impacted by a combination of genetic, genomic, and epigenetic pathways. We hypothesize that characterization of gene-specific DNA methylation marks will provide important insights into the factors contributing to CMS. We also hypothesize that characterizing DNA methylation marks correlated with ABCG1, CPT1A, and TXNIP variants may provide important insights into the regulation of these key cardiometabolic genes, previously determined to be important in CMS. Thus, the broad goals of this project include three specific aims to be carried out in the San Antonio Family Heart Study (SAFHS) cohort of 600 Mexican Americans: 1) To determine the association of quantitative methylation data from ABCG1, CPT1A, and TXNIP at baseline with prevalent diabetes-, hypertension-, and obesity-related phenotypes; 2) To determine the association of quantitative methylation data from ABCG1, CPT1A, and TXNIP at baseline with progression to diabetes, hypertension, and obesity over four study visits; and 3) To integrate single nucleotide polymorphism (SNP) variation, methylation marks, and gene expression data to define the most comprehensive causal model of CMS. The expected outcome of the proposed research and training is preliminary data to inform the design of a larger study led by the applicant to assess racial/ethnic variation in the epigenetics of CMS. In summary, this Mentored Career Development Award will foster the candidate's professional development as an independent scientist by providing an opportunity to gain expertise in epigenomics, health disparities, and statistical genetics. (End of Abstract)